The present invention relates to novel benzothiadiazoles and derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the invention provides a compound of formula I 
wherein
X is O, S, Nxe2x80x94CH3, CHxe2x95x90CH or CAlkxe2x95x90CAlk, where the Alk independently are (C1-4)alkyl,
R1 and R2 independently, are hydrogen, halogen, (C1-4)alkyl, (C1-4)alkoxy or trifluoromethyl, and
Het is a radical having one of the formulae (a) to (p) below: 
wherein
R3 and R8, independently, are hydrogen or (C1-4)alkyl,
R4 is hydrogen, halogen, (C1-4)alkyl, cyano, nitro, formyl or (C1-4)alkylcarbonyl,
R5 and R6, independently, are hydrogen, (C1-7)alkyl, (C3-7)alkenyl, (C3-7)cycloalkyl, (C3-7)cyclo (C1-4)alkyl, (C1-4)alkoxy(C2-5)alkyl or benzyl,
R7 is hydrogen, hydroxy, (C1-4)alkyl or (C1-4)alkoxy,
W is N, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94COH or Cxe2x80x94COxe2x80x94Alk where Alk is as defined above, and
X is as defined above,
in free base or acid addition salt form.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The radical Het is preferably located on a carbon atom which is adjacent to the heterocyclic moiety in formula I. Preferably Het is of formula (a) to (k), particularly of formula (a).
In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, whereby a compound of formula II 
wherein X, R1 and R2 are as defined above and Y is a radical having one of the formulae (axe2x80x2) to (pxe2x80x2) below: 
wherein R3 to R8, W and X are as defined above and Hal is halogen, is reacted with a compound of formula III 
wherein R5 and R6 are as defined above, and the resulting compound is recovered in free base form or in acid addition salt form.
The reaction may be effected in known manner, e.g. as described in Example 1. Hal is preferably chlorine, bromine or iodine, particularly chlorine.
Working up of the reaction mixtures obtained according to the above process and purification of the compounds thus obtained may be carried out in accordance to known procedures.
Acid addition salts may be produced in known manner from the free base forms and vice-versa. Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include for example the hydrochloride, the hydrogen maleate, the hydrogen fumarate and the hydrogen malonate.
The starting materials of formula II may be obtained as follows:
Compounds of formula II wherein Y is a radical having one of the formulae (axe2x80x2) and (dxe2x80x2), may be obtained by reacting a compound of formula IV 
wherein X, R1 and R2 are as defined above, with a compound of formula Va or Vd 
wherein R3 and R4 are as defined above and the Hal independently are halogen.
Compounds of formula II wherein Y is a radical having one of the formulae (bxe2x80x2), (cxe2x80x2) and (exe2x80x2) to (lxe2x80x2) may be obtained by reaction of POCl3 with a compound of formula VI 
wherein Yxe2x80x2 is a radical having one of the formulae (bxe2x80x3), (cxe2x80x3) and (exe2x80x3) to (lxe2x80x3) below 
wherein R3, R4, R7, R8 and W are as defined above.
All the above mentioned reactions are conventional.
The compounds of formulae III, IV, Va, Vd and VI are know or may be obtained from known compounds, using conventional procedures.
Compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro using corticotropine releasing factor (CRF) receptor expressing cell cultures, and in animals, and are therefore useful as pharmaceuticals.
In particular the agents of the invention bind to CRF receptors. More particularly they exhibit antagonistic activity at CRF1 receptors, as determined in vitro in the following assay:
Chinese hamster ovary (CHO) cells expressing human recombinant CRF1 (Chen et al., Proc Natl Acad Sci USA 90, 8967-8971, 1993) are propagated in Dulbecco""s modified Eagle medium supplemented with 10% foetal calf serum, non-essential aminoacids, 100 U/ml penicillin, 100 mg/l streptomycin and 1 g/l geneticin (G418). For cyclic AMP determinations, cells are grown to confluence in 24-multiwell plates. Stimulation of cyclic AMP accumulation by CRF (human/rat form) is measured in intact cells, using the [3H]adenine labelling technique, as described previously (Schoeffter et al., Neuropharmacology 36, 429-437, 1997). Concentration-response curves for CRF are constructed in the presence of putative antagonists (10 xcexcM) or vehicle (dimethyl sulfoxide 1% vol). KB values are calculated from the rightward shifts of the control curve, according to the formula: KB=[antagonist, M]/concentration-ratio-1), where the concentration-ratio designates the ratio of CRF EC50 value in the presence/CRF EC50 value in the absence, of antagonist [Furchgott, In: catecholamines (edited by Blaschko H and Muscholl E) pp. 283-335. Springer, Berlin, 1972].
In this test, the agents of the invention show CRF1 antagonistic activity with Kb CRF1 values of about 1 to 500 nM.
The agents according to the invention are therefore useful in the treatment of any state with increased endogenous level of CRF or in which the HPA (hypothalamic pituitary axis) is disregulated, or of various diseases induced or facilitated by CRF, including inflammatory disorders, such as arthritis, asthma and allergies; anxiety including generalized anxiety; phobic and panic attacks; depression; fatigue syndrome; headache; pain, e.g. inflammatory or neuropathic pain; cancer; irritable bowel syndrome, including Crohn""s disease, spastic colon and irritable colon; immune dysfunction; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as senile dementia, Alzheimer""s disease and Parkinson""s disease; stroke and head trauma; epilepsy; gastrointestinal diseases; eating and body weight disorders such as obesity and anorexia nervosa; hemorrhagic stress; drug and alcohol withdrawal symptoms; drug addiction; sleeping disorders; hormonal disregulations; skin disorders; stress-induced psychotic episodes; fertility problems; sexual dysfunctions and pre-term birth.
The utility of the agents of the invention in the above indicated diseases could be confirmed in a range of standard tests:
For example the anxiolytic activity of the agents of the invention could be confirmed in the mouse elevated plus-maze [see for example Rodgers R. J., Behavioural Pharmacology 8: 477-496 (1997) where the relevance of the elevated plus-maze is discussed on p. 486; for the method, see Rodgers R. J. et al. Ethology and Psychopharmacology (Eds S J Cooper and C A Hendrie), pp 9-44 (1994), J. Wiley, Chichester]. In this test, the agents of the invention show anxiolytic-like effects on administration of 0.1 to 30 mg/kg p.o.
For the above-mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of an agent of the invention, conveniently administered, for example, In divided doses up to four times a day or in sustained release form.
The agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
For the above-mentioned indications a preferred compound is the compound of Example 1 below. In the above-described binding test said compound exhibits CRF1 antagonistic activity with a Kb CRF1 of 36 nM. In the above-described elevated plus-maze, doses of 0.1 to 10 mg/kg p.o. (with a maximum at 3 mg/kg) significantly affect the anxiety-related behavioural parameters. In contrast to the standard chlordiazepoxide, parameters related to motor stimulation are not affected, which indicates that the observed anxiolytic effects are not attributable to a general motor stimulation.
In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of diseases induced or facilitated by CRF, such as these indicated above.
The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of a compound according to the invention.
Moreover the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above.
In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected.